Understanding of the molecular mechanisms of drug addiction is essential for the development of novel approaches for the treatment of this debilitating disease. Recent findings showed that development of addictive behavior in mice is associated with stable changes in gene expression. The genetic basis of addiction raises the question about the nature of genes and their regulators that play a critical role in addiction. We found that establishment of cocaine addiction in mice is associated with expression changes of numerous miRNAs in the striatum, a brain area responsible for drug addiction. Given the potent role of miRNAs in regulation of gene expression, we hypothesize that cocaine regulated miRNAs contribute to the establishment of the gene expression network that supports addiction. To evaluate the contribution of cocaine induced miRNAs to the development and maintenance of cocaine addiction we propose to address the impact of striatum specific alteration of individual miRNAs on addiction. The two most well defined symptoms of addiction in mice such as cocaine induced sensitization and reward will be used to address the role of miRNA on animal behavior. We will test whether correction of miRNA levels affected by chronic cocaine treatment affects the development of addictive behavior in vivo. Inactivation of miRNA that are induced by cocaine treatment will be achieved by injection of the RNA based cell-permeable specific miRNA inhibitors into the striatum. In turn, striatum specific normalization of miRNA that are suppressed by cocaine will be achieved by using miRNA expressing adenoassociated virus (AAV). Identification of specific miRNAs that play a role in the development and maintenance of cocaine addiction may help to reveal molecular networks controlling dopamine signaling in health and disease. Furthermore, targeting of the addiction-associated miRNAs by synthetic miRNA antagonists may lead to development of novel and highly specific approach for treatment of addiction. PUBLIC HEALTH RELEVANCE: The widespread and sociomedical impact of drug addiction dictates the necessity to develop efficient and selective drugs for the treatment of this harmful disease. In our studies we propose to explore the possibility of selective correction of gene function for the purpose of anti-addictive therapy. We found that the development of addiction is associated with aberrant expression of miRNAs, a novel class of highly potent and equally selective regulators of gene expression. We will test whether normalization of the miRNA expression, altered by cocaine treatment, will normalize brain function and cure addiction.